INDICATION AND IMPORTANT SAFETY INFORMATION FOR ULTANE^® (sevoflurane)

INDICATION¹

• ULTANE® (sevoflurane) is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. ULTANE should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of ULTANE should be used.

IMPORTANT SAFETY INFORMATION¹

• ULTANE can cause malignant hyperthermia. Postmarketing reports of malignant hyperthermia, some of which have been fatal, have occurred. ULTANE should not be used in patients with known sensitivity to sevoflurane or to other halogenated agents, or in patients with known or suspected susceptibility to malignant hyperthermia.
• Findings taken from patient and animal studies suggest that there is a potential for renal injury when ULTANE is used at low flow rates, which is presumed due to Compound A. The level of Compound A exposure at which clinical nephrotoxicity might be expected to occur has not been established. To minimize exposure to Compound A, ULTANE exposure should not exceed 2 MAC-hours at flow rates of 1 to <2 L/min. Fresh gas flow rates <1 L/min are not recommended.
• Because clinical experience in administering ULTANE to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.
• ULTANE may be associated with glycosuria and proteinuria when used for long procedures at low flow rates.
• KOH containing CO₂ absorbents are not recommended for use with ULTANE. An exothermic reaction occurs when ULTANE is exposed to CO₂ absorbents. This reaction is increased when the absorbent becomes desiccated. Rare cases of extreme heat, smoke, and/or spontaneous fire have been reported during ULTANE use in conjunction with the use of desiccated CO₂ absorbent, specifically those containing potassium hydroxide (e.g., Baralyme).
• Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering ULTANE to susceptible patients (e.g. patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).
• Rare increases in serum potassium resulting in cardiac arrhythmias and death have been noted in pediatric patients during the postoperative period following the use of inhaled anesthetic agents. Contributing risk factors appear to be latent or overt neuromuscular disease, particularly Duchenne muscular dystrophy. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. Early, aggressive intervention to treat both hyperkalemia and resistant arrhythmias, and subsequent evaluation for latent neuromuscular disease, is recommended.
• Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in the third trimester of gestation through the first three years of age may result in adverse cognitive or behavioral effects on their developing brains. The studies in children have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors, such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children when needed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
• Due to ULTANE’s insolubility in blood, hemodynamic changes may occur more rapidly than with other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of ULTANE.
• Seizures have been reported in association with ULTANE use, the majority of which have occurred in children and young adults, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using ULTANE in patients who may be at risk for seizures.
• Drug interactions: Benzodiazepines and opioids would be expected to decrease the MAC of ULTANE. The anesthetic requirement for ULTANE is decreased when administered in combination with nitrous oxide. ULTANE increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants.
• Very rare cases of mild, moderate, and severe postoperative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences. In addition, rare postmarketing reports of hepatic failure and hepatic necrosis have been associated with the use of ULTANE. Clinical judgment should be used in patients with underlying hepatic conditions or who are under treatment with drugs known to cause hepatic dysfunction. It has been reported that previous exposure to halogenated hydrocarbon anesthetics may increase the potential for hepatic injury.
• Adverse events reported by ≥5% of the surgical patients receiving ULTANE during clinical trials during induction included: bradycardia, tachycardia, agitation, laryngospasm, airway obstruction, breathholding, and increased cough; during maintenance and emergence: shivering, hypotension, bradycardia, somnolence, agitation, nausea, vomiting, and increased cough were reported.
  

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INDICATION AND IMPORTANT SAFETY INFORMATION for MIVACRON^® (mivacurium chloride)

INDICATION²

• MIVACRON^® (mivacurium chloride) injection is a short-acting neuromuscular blocking agent indicated for inpatients and outpatients, as an adjunct to general anesthesia, to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

IMPORTANT SAFETY INFORMATION²

• MIVACRON is contraindicated in patients with known hypersensitivity to the product and its components.
• Severe anaphylactic reactions to neuromuscular blocking agents, including MIVACRON, have been reported. These reactions have in some cases been life-threatening and fatal. Necessary precautions, including the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents.
• MIVACRON should only be administered intravenously in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with the drug’s actions and the possible complications.
• It is recommended that a peripheral nerve stimulator be used during the administration of MIVACRON to monitor drug effect, determine the need for additional drug, and confirm recovery from neuromuscular block.
• MIVACRON has no known effect on consciousness, pain threshold, or cerebration.
• MIVACRON is metabolized by plasma cholinesterase and should be used with great caution, if at all, in patients suspected of being homozygous for the atypical plasma cholinesterase gene due to the possibility of prolonged neuromuscular block. Plasma cholinesterase activity may be diminished in patients with genetic abnormalities of plasma cholinesterase, pregnancy, liver or kidney disease, malignant tumors, infections, burns, anemia, decompensated heart disease, peptic ulcer, or myxedema. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase.
• Exercise caution when administering MIVACRON to patients with clinically significant cardiovascular disease, obesity, or any history suggesting sensitivity to the release of histamine (e.g., asthma), as a transient decrease in mean arterial pressure related to histamine release is possible.
• MIVACRON will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.
• Doses of MIVACRON should be individualized for drugs or conditions causing potentiation of or resistance to neuromuscular block. The following may cause potentiation: neuromuscular diseases, burns, acid-base and/or serum electrolyte abnormalities, cachexia, debilitation, and carcinomatosis. The following may cause resistance: burns, acid-base and/or serum electrolyte abnormalities, and chronic administration of phenytoin or carbamazepine.
• Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC decreases the ED₅₀ of MIVACRON. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, quinidine, and succinylcholine.
• Adverse events: >1% of the surgical patients treated with MIVACRON during clinical trials reported flushing (16%); <1% of patients reported hypotension, tachycardia, bradycardia, cardiac arrhythmia, phlebitis, bronchospasm, wheezing, hypoxemia, rash, urticaria, erythema, injection site reaction, prolonged drug effect, dizziness, or muscle spasms.

Please see the full Prescribing information for MIVACRON.
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch call 1-800-FDA-1088.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR NIMBEX^® (cisatracurium besylate)

INDICATION³

• NIMBEX^® (cisatracurium besylate) is an intermediate-onset/intermediate-duration neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the ICU.

IMPORTANT SAFETY INFORMATION³

• NIMBEX is contraindicated in patients with known hypersensitivity to the product and its components. The 10-mL multiple-dose vials of NIMBEX are contraindicated for use in premature infants because the formulation contains benzyl alcohol.
• Severe anaphylactic reactions to neuromuscular blocking agents, including NIMBEX, have been reported. These reactions have in some cases been life-threatening and fatal. Precaution should be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents.
• NIMBEX should only be administered intravenously in carefully adjusted dosage by or under the supervision of experienced clinicians familiar with the drug’s actions and possible complications.
• It is recommended that a peripheral nerve stimulator be used during the administration of NIMBEX to monitor drug effect, determine the need for additional doses, and confirm recovery from neuromuscular block.
• NIMBEX has no known effect on consciousness, pain threshold, or cerebration.
• The 10-mL multiple-dose vials of NIMBEX contain benzyl alcohol, which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity, particularly in preterm infants and neonates, and there have been rare reports of deaths, primarily in preterm infants. The minimum amount of benzyl alcohol at which toxicity may occur is not known. The practitioner must consider the daily metabolic load of benzyl alcohol from medications containing this preservative. Single-use vials (5-mL and 20-mL) of NIMBEX do not contain benzyl alcohol. NIMBEX has not been studied in pediatric patients below the age of 1 month.
• NIMBEX has an intermediate onset of action and is not recommended for rapid sequence endotracheal intubation.
• NIMBEX will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.
• Doses should be individualized for conditions causing potentiation of or resistance to neuromuscular block, such as in patients with neuromuscular diseases, burns, hemiparesis or paraparesis, acid-base and/or serum electrolyte abnormalities, and in patients receiving chronic treatment with phenytoin or carbamazepine.
• Long-term infusion (up to 6 days) of NIMBEX during mechanical ventilation in the ICU has been safely used in 2 studies. Use in the ICU for longer than 6 days has not been studied. Dosage requirements may increase or decrease with time. Whenever the use of NIMBEX in the ICU is contemplated, it is recommended that neuromuscular function be monitored during administration with a nerve stimulator. Additional doses of NIMBEX or any other neuromuscular blocking agent should not be given before there is a definite response to nerve stimulation. If no response is elicited, infusion administration should be discontinued until a response returns.
• The time to onset of maximum block following NIMBEX is approximately 2 minutes faster with prior administration of succinylcholine.
• Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC may prolong the clinically effective duration of action and decrease the required infusion rate of NIMBEX. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as NIMBEX include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistemethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine.
• No adverse event was reported by >1% of the surgical patients treated with NIMBEX during clinical trials; <1% of patients reported bradycardia, hypotension, flushing, bronchospasm, and/or rash.
• Adverse experiences were uncommon among the 68 ICU patients who received NIMBEX in conjunction with other drugs in US and European clinical studies. One out of 68 patients experienced bronchospasm. In one study, there were 2 reports of prolonged recovery among 28 patients administered NIMBEX compared with 13 reports among 30 patients administered vecuronium.

Please see the full Prescribing information for NIMBEX.
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

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References: 1. ULTANE [package insert]. North Chicago, IL: AbbVie Inc. 2. MIVACRON [package insert]. North Chicago, IL: AbbVie Inc. 3. NIMBEX [package insert]. North Chicago, IL: AbbVie Inc.